Abstract
BackgroundNeurofibromatosis type 1 (NF1) is a common dominant tumor predisposition syndrome affecting 1 in 3,500 individuals. The hallmarks of NF1 are the development of peripheral nerve sheath tumors either benign (dermal and plexiform neurofibromas) or malignant (MPNSTs).ResultsTo comprehensively characterize the role of microRNAs in NF1 tumorigenesis, we analyzed 377 miRNAs expression in a large panel of dermal and plexiform neurofibromas, and MPNSTs. The most significantly upregulated miRNA in plexiform neurofibromas was miR-486-3p that targets the major tumor suppressor gene, PTEN. We confirmed PTEN downregulation at mRNA level. In plexiform neurofibromas, we also report aberrant expression of four miRNAs involved in the RAS-MAPK pathway (miR-370, miR-143, miR-181a, and miR-145). In MPNSTs, significant deregulated miRNAs were involved in PTEN repression (miR-301a, miR-19a, and miR-106b), RAS-MAPK pathway regulation (Let-7b, miR-195, and miR-10b), mesenchymal transition (miR-200c, let-7b, miR-135a, miR-135b, and miR-9), HOX genes expression (miR-210, miR-196b, miR-10a, miR-10b, and miR-9), and cell cycle progression (miR-195, let-7b, miR-20a, miR-210, miR-129-3p, miR-449a, and miR-106b).ConclusionWe confirmed the implication of PTEN in genesis of plexiform neurofibromas and MPNSTs in NF1. Markedly deregulated miRNAs might have potential diagnostic or prognostic value and could represent novel strategies for effective pharmacological therapies of NF1 tumors.
Highlights
Neurofibromatosis type 1 (NF1) is a common dominant tumor predisposition syndrome affecting 1 in 3,500 individuals
Inverse expression of miRNAs with their protein-coding gene targets Using Spearman’s rank correlation test, we reported that several upregulated miRNAs in malignant peripheral nerve sheath tumors (MPNST) compared to plexiform neurofibromas (PNFs) have significant inverse correlated expression with their previously identified target genes: HMGA2 mRNA expression is inversely correlated with let-7b (r = −0.387, P = 0.003) and PTEN expression is inversely correlated with miR-301a (r = −0.67, P = 5.9.10-8), miR-19a (r = −0.67, P = 6.4.10-8), and miR-106b (r = −0.65, P = 1.5.10-7)
Our work highlights the key role of miRNAs in NF1-associated tumorigenesis, leading to subtle reductions in PTEN levels
Summary
Neurofibromatosis type 1 (NF1) is a common dominant tumor predisposition syndrome affecting 1 in 3,500 individuals. The hallmarks of NF1 are the development of peripheral nerve sheath tumors either benign (dermal and plexiform neurofibromas) or malignant (MPNSTs). According to the Knudson’s two-hit model, NF1 tumorigenesis results from a somatic mutation disrupting the second functional copy of the NF1 gene. This complete inactivation of NF1 induces RAS signaling pathway activation and seems required but not sufficient for tumorigenesis promotion. Expression studies have reported differential expression profile in MPNSTs of genes involved in cell proliferation, apoptosis, invasion, extracellular remodeling and Schwann cell differentiation such as TP53, RB1, CDKN2A, TWIST1, BIRC5, TOP2A, and SOX9 [4,5,6]. Transgenic mouse models have provided evidences for TP53 and PTEN implication in PNFs formation and Schwann cells malignant transformation [7,8]
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